1. Field of the Invention
The present invention relates to formulations in form of an aqueous suspension of drug particles of a corticosteroid. The present invention also relate to the use of such a formulation for topical administration for the prophylaxis and/or treatment of a dermatological disease such as atopic dermatitis, acne and psoriasis. The present invention also relates to processes for preparing such a formulation and methods of administering such a formulation onto the skin, in the form of a spray.
2. Discussion of the Background
In humans, the skin is the largest organ of the integumentary system, i.e. system that protects the body from damage. It is made of three main layers, i.e.: i) the epidermis which is the most superficial layer of skin, and is principally constituted of keratinocyte cells; ii) the dermis, which is the intermediate layer constituted of collage, elastic fibers, and extrafibrillar matrix; and iii) the subcutaneous tissue which is a deep layer of fat underlying the fascia.
There are many conditions or diseases that could affect the skin collectively known as dermatitis or dermatoses. Dermatitis symptoms vary with all different forms of the condition. They range from skin rashes to bumpy rashes or including blisters.
The prevention or treatment of disease states or conditions of the skin has traditionally used simple local delivery systems. In particular, topical corticosteroids, such as bethametasone 17-valerate, bethametasone dipropionate, and beclometasone dipropionate, are widely used as active ingredients primarily because of their anti-inflammatory, antipruritic, and vasoconstrictive actions.
Current corticosteroid-containing products are available mainly as aerosol foams, creams, gels, lotions, shampoos, or ointments that are supplied in tubes or bottles and applied to an affected area of the skin by hand (finger tips).
Many formulations such as creams, lotions, or ointments are greasy, and hence are unpleasant to apply on large areas of the skin. Moreover, the ineffectiveness of said formulations is also observed, since they are generally too viscous to allow efficient penetration of the active agent in the epidermis. In addition, some conventional cream and ointment bases are irritating to the skin, particularly over the long exposure that is frequently required for efficacy, and the fluidity of lotions often makes the physical application difficult to control over a desired area. Moreover, it is necessary to rub such formulations into the target site to improve the penetration of the active agent into the epidermis, an action which itself produces irritation. Furthermore, sensitization by the formulation components to environmental agents (e.g. U.V. rays) has always to be taken into account.
The formulations in form of pressurized aerosol (propellant based) formulations often contain ethanol and hence they suffer of the well known adverse effects of ethanol, i.e., irritation. Additionally, said formulations have the disadvantage of relatively high cost, primarily due to the construction of the containers and metering valves. Other formulations contain other irritant vehicles or solvents such as propylene glycol, and hence such formulations do not promote patient compliance.
Several formulations are also available that cause substantial foam formation upon spraying onto the skin, which is highly undesirable to a patient using such preparations for aesthetic reasons.
Moreover, it should be highlighted that in many skin diseases the process of keratinization is disturbed resulting in an increased transepidermal water loss. A consequence of this can be poor skin structure leading to bacterial infection, penetration of allergens or toxic materials as well as increased water loss further exacerbating the disease.
To overcome this problem, an occlusive barrier constituted of a plastic film is often applied to the skin during application to enhance the retention of the moisture. A commonly used film is composed of a polyvinylidene chloride (PVDC) copolymer. This way of occluding the surface of the skin, however, is difficult to administer and contraindicated in certain skin diseases such as psoriasis.
Alternatively, moisturizing agents are sometimes added, but some of these excipients may be irritants and not well-tolerated so much as that some of the relevant formulation may also contain soothing agents that prevent irritation such as aloe, green tea, chamomile, licorice root, or allantoin.
A further disadvantage of conventional formulations is that their active agents act for a short duration of time and do not efficaciously reach the deeper derma stratum but only penetrate into the superficial epidermis.
They thus require frequent re-application, thereby providing a negative impact on treatment compliance and quality of life of the patient, with often a enhancement of drop out due to the lack of compliance.
Furthermore, the presence of high levels of corticosteroids in the superficial epidermis may cause undesired effects such as thinning of the skin (atrophy), which sometimes results in unaesthetic permanent stretch marks (striae).
In summary, the disadvantages of topical corticosteroid-based formulations vary, in that they can often irritate normal skin, be time consuming and awkward to apply, cannot be used for long periods, can stain clothing, and/or have an objectionable odor.
As a result, it is sometimes difficult for people to maintain regular applications of these medications.
On the other hand, sudden withdrawal of corticosteroids can cause an aggressive recurrence of the condition. This is known as “rebound” of the condition.
Topical formulations free of some of the aforementioned disadvantages are disclosed in WO 2011/026076, which is incorporated herein by reference in its entirety. However, its teaching is substantially directed to the preparation of oil-in-water emulsion wherein the corticosteroid, being hydrophobic, would be dissolved in the oil phase, making it more prone for absorption.
In addition, to favor the penetration of the active ingredient in the derma and hence its efficacy, in the formulations of WO 2011/026076, significant amounts of surfactant agents and penetration enhancers are added. Both of these features could contribute to significantly increase the penetration of the active agent not only into the derma but also in the subcutaneous tissue, which in turn could give rise to an increased absorption into the bloodstream.
On the other hand, it is known that the side-effects of corticosteroids mainly occur at the systemic level, and that children in particular, are at a higher risk of systemic side effects. Such effects are dose dependent at topical as well as systemic levels. It means that, as a general therapeutical agreement, the optimal dosing schedule is that which, with the minimum dosage, still provides efficacy (mostly relief of symptoms).
Moreover, it is known that a high amount of certain surfactant agents could be irritating due to their capacity of sequestering lipids, that are important components of the hydrophobic water-protective barrier of the skin.
There remains, therefore, an unmet need for improved patient compliant topical formulations that are effective in the treatment of skin disorders.